Agonists of the mu-opioid receptor, such as morphine, are some of the most effective and widely used drugs in the treatment of pain. However, these compounds also have significant effects that limit their therapeutic potential such as the development of tolerance and dependence. One area of interest that has arisen in the search for ways to reduce these unwanted effects involves combining the administration of opioid compounds with drugs that act directly on different systems, but also interact with the opioid system. Ideally, such combinations would enhance the antinociceptive effects of the opioid without increasing unwanted effects. The cannabinoid system interacts with the opioid system and manipulations of cannabinoid signaling may have the potential to be used in this manner. Indeed, cannabinoid agonists have been shown to enhance the antinociceptive effects of opioids such as morphine. However, there is evidence that suggests that cannabinoid/opioid agonist combinations may also produce unwanted effects. For instance, cannabinoid agonists have been shown to enhance the effects of opioids that are associated with their abuse potential. Direct activation of the receptor is not the only way to alter the activity of the cannabinoid system. Recent evidence suggests that altering cannabinoid signaling by manipulating the metabolism and uptake of endogenous cannabinoids, such as anandamide, may hold a therapeutic potential. For intance, altering cannabinoid signaling in this manner produces antinociception, but does not produces some of the unwanted effects associatedwith the administration of cannabinoid agonists. The experiments proposed here build upon these observations by determining whether compounds that inhibit the transport or metabolism of endocannabinoids can enhance the acute antinociceptive effects of morphine (Specific Aim I), and alter the development of tolerance to morphine's antinociceptive effects (Specific Aim II). The experiments described in this proposal will extend existing knowledge regarding the role of the cannabinoid system as a therapeutic target in the treatment of pain. The proposal is also comprised of investigations that are designed to address questions related to the abuse potential of drugs. Findings from these experiments may provide insights that translate to clinical applications.